2′-C-Alkylribonucleosides have been described in the patent literature as inhibitors of HCV RNA-dependent RNA polymerase and thereby useful for the treatment of HCV infection. Reference is made to the following publications of international patent applications which disclose branched-chain ribonucleoside inhibitors of HCV polymerase: WO 01/90121 (29 Nov. 2001) and WO 01/92282 (6 Dec. 2001) both assigned to Novirio Pharmaceuticals and Universita degli Studi di Cagliari; WO 02/32920 (25 Apr. 2002) assigned to Pharmasset Limited; WO 02/057287 (25 Jul. 2002) and WO 02/057425 (25 Jul. 2002) both assigned jointly to Merck & Co. and Isis Pharmaceuticals. Synthetic approaches to 2′-C-branched ribonucleosides have previously been described in the chemical and patent literature: U.S. Pat. No. 3,480,613 (25 Nov. 1969); S. R. Jenkins et al. Carbohydr. Res., 166: 219–232 (1987); M. S. Wolfe et al., “A Concise Synthesis of 2′-C-Methylribonucleosides,” Tetrahedron Lett., 42: 7611–7614 (1995); R. E. Harry-O'kuru et al., “A Short, Flexible Route Toward 2′-C-branched Ribonucleosides,” J. Org. Chem., 62: 1754–1759 (1997); Y. Murai et al., “A Synthesis and X-Ray Analysis of 2′-C-, 3′-C-, and 5′-C-Methylsangivamycins,” Heterocycles, 33: 391–404 (1992); and M. Gallo et al., “Synthesis of 2′-Modified Nucleotides,” Molecules, 5: 727–729 (2000). Although the synthetic methods disclosed in these references suffice to prepare small quantities of the desired branched-chain ribonucleosides, they suffer from low and variable yields in the key glycosylation step to elaborate the nucleosidic bond in a stereoselective fashion and therefore are not amenable from an economic perspective to scale-up for the production of kilogram quantities required for preclinical and clinical use.
The present invention provides a novel process to partially protected ribofuranose sugar derivatives from inexpensive starting materials which can be further elaborated into the desired 2′-C-alkylribonucleosides having anti-HCV properties. The instant process makes use of crystalline intermediates to eliminate chromatographic purification steps resulting in considerably improved yields of the final compounds. The invention also provides novel diol intermediates that result from the instant process.